PRODUCT MONOGRAPH. Cabazitaxel for injection. Concentrated Solution 40 mg/ml (60 mg/1.5 ml) Antineoplastic Agent L01CD04

Transcription

1 PRODUCT MONOGRAPH Pr JEVTANA Cabazitaxel for injection Concentrated Solution 40 mg/ml (60 mg/1.5 ml) Antineoplastic Agent L01CD04 sanofi-aventis Canada Inc Place Louis-R.-Renaud Laval, Quebec H7V 0A3 Date of Revision: April 22, 2014 Submission Control No.: s-a Version 6.0 dated April 22, 2014 Page 1 of 43

2 Table of Contents PART I: HEALTH PROFESSIONAL INFORMATION...3 SUMMARY PRODUCT INFORMATION...3 INDICATIONS AND CLINICAL USE...3 CONTRAINDICATIONS...4 WARNINGS AND PRECAUTIONS...4 ADVERSE REACTIONS...9 DRUG INTERACTIONS...15 DOSAGE AND ADMINISTRATION...17 OVERDOSAGE...24 ACTION AND CLINICAL PHARMACOLOGY...24 STORAGE AND STABILITY...27 SPECIAL HANDLING INSTRUCTIONS...28 DOSAGE FORMS, COMPOSITION AND PACKAGING...28 PART II: SCIENTIFIC INFORMATION...30 PHARMACEUTICAL INFORMATION...30 CLINICAL TRIALS...31 DETAILED PHARMACOLOGY...36 TOXICOLOGY...38 REFERENCES...40 PART III: CONSUMER INFORMATION...41 Page 2 of 43

3 Pr JEVTANA (cabazitaxel for injection) PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Administration Intravenous infusion Dosage Form / Strength Concentrated solution/ 40 mg/ml Clinically Relevant Nonmedicinal Ingredients Polysorbate 80 Diluent 13% (w/w) ethanol in water for injection INDICATIONS AND CLINICAL USE JEVTANA (cabazitaxel) in combination with prednisone or prednisolone is indicated for the treatment of patients with castration resistant (hormone refractory) metastatic prostate cancer previously treated with a docetaxel containing regimen. JEVTANA should only be administered by a qualified healthcare professional experienced in the use of antineoplastic therapy (see DOSAGE AND ADMINISTRATION and SPECIAL HANDLING INSTRUCTIONS sections). Geriatrics ( 65 years of age): Evidence from clinical studies suggests that use in the geriatric population is associated with differences in safety and a brief discussion can be found in the appropriate sections (see WARNINGS AND PRECAUTIONS, Special Populations, ADVERSE REACTIONS, Clinical Trial Adverse Reactions, Special Populations, DOSAGE AND ADMINISTRATION, Special Populations, ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions). Pediatrics (< 16 years of age): The safety and the efficacy of JEVTANA in children have not been established. Page 3 of 43

4 CONTRAINDICATIONS JEVTANA is contraindicated in patients with: a history of severe hypersensitivity reactions to cabazitaxel or other drugs formulated with polysorbate 80, or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage forms, Composition and Packaging section of the Product Monograph. neutrophil counts 1500/mm 3 ; hepatic impairment (bilirubin 1 x Upper Limit of Normal (ULN), or AST/SGOT and/or ALT/SGPT 1.5 ULN). concomitant vaccination with yellow fever vaccine (see DRUG INTERACTIONS section). WARNINGS AND PRECAUTIONS Serious Warnings and Precautions Box JEVTANA should only be administered by a qualified healthcare professional experienced in the use of antineoplastic therapy (see INDICATION AND CLINICAL USE section). Severe hypersensitivity, pre-medication is recommended prior to treatment (see Immune section below and DOSAGE AND ADMINISTRATION). Neutropenic death/neutrophil count (see WARNINGS AND PRECAUTIONS). Gastrointestinal (GI) hemorrhage and perforation, including fatal cases, particularly in patients most at risk of developing gastrointestinal complications (see WARNINGS AND PRECAUTIONS). General Driving a vehicle or performing other hazardous tasks No studies on the effects on the ability to drive and use machines have been performed. However, based on the safety profile, JEVTANA may have moderate influence on the ability to drive and use machines as it may cause fatigue and dizziness. Patients should be advised not to drive or use machines if they experience these adverse reactions during treatment. Page 4 of 43

5 Cardiovascular There is pre-clinical evidence that cabazitaxel may prolong the QT interval (see DETAILED PHARMACOLOGY, Cardiovascular Safety Pharmacology section). To further investigate the effect of cabazitaxel on QT interval, an open-label trial was conducted. No large changes in the mean QT interval (i.e., > 20 ms) from baseline based on Fridericia correction method were detected. However, a small increase in the mean QTc interval (i.e., < 10 ms) cannot be excluded due to study design limitations. Cardiac arrhythmias have been reported in patients treated with JEVTANA, most commonly tachycardia and atrial fibrillation. During the randomized clinical trial, 4 fatal cases related to cardiac events were reported, although none was considered related to JEVTANA by the investigator (see ADVERSE REACTIONS, Clinical Trial Adverse Reactions, Cardiac disorders and arrhythmias section). Gastrointestinal Gastrointestinal symptoms If patients experience diarrhea following administration of JEVTANA they should be treated with commonly used anti-diarrheal medications. Appropriate measures should be taken to rehydrate the patients to avoid complications such as dehydration and electrolyte imbalance. Treatment delay or dosage reduction may be necessary for grade 3 diarrhea (see DOSAGE AND ADMINISTRATION section). During the randomized clinical trial, one fatal case was due to electrolyte imbalance (see ADVERSE REACTIONS, Clinical Trial Adverse Reactions, Gastrointestinal section). If patients experience nausea or vomiting, they may be treated with commonly used anti-emetics. Gastrointestinal (GI) hemorrhage and perforation, ileus, colitis, including fatal outcome, have been reported in patients treated with cabazitaxel. Caution is advised with treatment of patients most at risk of developing gastrointestinal complications: those with neutropenia, the elderly, concomitant use of NSAIDs, anti-platelet therapy or anti-coagulants, and patients with a prior history of pelvic radiotherapy, gastrointestinal disease, such as ulceration and GI bleeding. Symptoms such as abdominal pain and tenderness, fever, persistent constipation, diarrhoea, with or without neutropenia, may be early manifestations of serious gastrointestinal toxicity and should be evaluated and treated promptly. Cabazitaxel treatment delay or discontinuation may be necessary. Hematologic Anemia Caution is recommended in patients with anemia and appropriate measures should be taken as clinically indicated. Page 5 of 43

6 Neutropenia During the randomized clinical trial, five patients experienced fatal infectious adverse events (sepsis or septic shock). All had grade 4 neutropenia and one had febrile neutropenia. One additional patient death was attributed to neutropenia without a documented infection (see ADVERSE REACTIONS, Clinical Trial Adverse Reactions, Abnormal Hematologic and Clinical Chemistry Findings section). Neutropenia is the most common adverse reaction of JEVTANA (see ADVERSE REACTIONS section). Ongoing patient monitoring is required from the first cycle and throughout treatment. Monitoring of complete blood count is essential on a weekly basis during cycle 1 and before each treatment cycle and as required thereafter so that the dose can be adjusted, if needed (See Monitoring and Laboratory Tests section). Reduce dose in case of febrile neutropenia, or prolonged neutropenia despite appropriate treatment (see DOSAGE AND ADMINISTRATION section). Re-treat only when neutrophils recover to a level > 1500/mm 3 (see CONTRAINDICATIONS section). Patients treated with JEVTANA may receive prophylactic G-CSF as per American Society of Clinical Oncology (ASCO) and/or current institutional guidelines, to reduce the risk or manage neutropenia complications (febrile neutropenia, prolonged neutropenia or neutropenic infection). Patients may also receive antibiotics when appropriate. The use of G-CSF has been shown to limit the incidence and severity of neutropenia. Hepatic JEVTANA is contraindicated in patients with hepatic impairment (bilirubin 1 x Upper Limit of Normal (ULN), or AST/SGOT and/or ALT/SGPT 1.5 ULN). JEVTANA is extensively metabolized in the liver, and hepatic impairment is likely to increase JEVTANA concentrations. Hepatic impairment is known to increase the risk of severe and lifethreatening complications in patients receiving other drugs belonging to the same class as JEVTANA. No formal pharmacokinetic studies in patients with hepatic impairment have been conducted. Effects on liver have been observed in pre-clinical settings (see DETAILED PHARMACOLOGY). Patients with impaired hepatic function (total bilirubin 1xULN, or AST and/or ALT 1.5x ULN) were excluded from the randomized clinical trial conducted in patients with metastatic hormone-resistant prostate cancer. Therefore, safety in this patient population is unknown. Immune Hypersensitivity reactions: All patients should be premedicated prior to the initiation of the infusion of JEVTANA (see DOSAGE AND ADMINISTRATION section). Page 6 of 43

7 Patients should be observed closely for hypersensitivity reactions especially during the first and second infusions. Hypersensitivity reactions may occur within a few minutes following the initiation of the infusion of JEVTANA, thus facilities and equipment for the treatment of hypotension and bronchospasm should be available. Severe reactions can occur and may include generalized rash/erythema, hypotension and bronchospasm. Severe hypersensitivity reactions require immediate discontinuation of JEVTANA and appropriate therapy. Patients who have a history of severe hypersensitivity reactions should not be rechallenged with JEVTANA (see CONTRAINDICATIONS section). Neurologic Cases of peripheral neuropathy, peripheral sensory neuropathy (e.g., paraesthesias, dysaesthesias) and peripheral motor neuropathy have been observed in patients receiving JEVTANA (see ADVERSE REACTIONS). Renal Renal disorders Renal disorders have been reported in association with sepsis, severe dehydration due to diarrhea, vomiting and obstructive uropathy. Renal failure including 4 cases with fatal outcome has been observed during the randomized clinical trial (see ADVERSE REACTIONS, Clinical Trials Adverse Drug Reactions, Renal section). Appropriate measures should be taken to identify the cause and intensively treat the patients if this occurs. Renal function should be monitored during JEVTANA therapy. Serum creatinine should be measured at baseline and with each blood count. JEVTANA treatment should be discontinued in case of renal failure grade 3 (see WARNINGS and PRECAUTIONS, Monitoring and Laboratory tests). Reproduction Due to potential exposure via seminal liquid, men with partners of childbearing potential should use reliable contraception throughout treatment and are recommended to continue this for up to 6 months after the last dose of JEVTANA. Men being treated with JEVTANA are advised to seek advice on conservation of sperm prior to treatment. Special Populations Geriatrics ( 65 years of age): Elderly patients may be more likely to experience certain adverse reactions including neutropenia and febrile neutropenia (see ADVERSE REACTIONS, Clinical Trial Adverse Reactions, Special Populations section). However no specific dose adjustment for the use of JEVTANA in elderly patients is recommended (see DOSAGE AND ADMINISTRATION, Special populations). Page 7 of 43

8 Pregnant Women: The effect of JEVTANA on human fertility is unknown. Animal studies showed that JEVTANA affected reproductive system in male rats and dogs (see TOXICOLOGY section). There are no data from the use of JEVTANA in pregnant women. JEVTANA crosses the placenta barrier. In non-clinical studies in rats and rabbits, JEVTANA was embryotoxic, fetotoxic and abortifacient at exposures significantly lower than those expected at the recommended human dose level (see TOXICOLOGY section). JEVTANA is not recommended during pregnancy. Nursing Women: Available pharmacokinetics data in animals have shown excretion of JEVTANA and its metabolites in milk (see TOXICOLOGY section). JEVTANA should not be used during breastfeeding. Pediatrics (< 16 years of age): The safety and the efficacy of JEVTANA in children have not been established. Patients with hepatic impairment: Treatment with JEVTANA is contraindicated in patients with hepatic impairment. (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION, Special Populations sections). JEVTANA is extensively metabolized in the liver and hepatic impairment is likely to increase JEVTANA concentrations (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions section). Hepatic impairment increases the risk of severe and life-threatening complications in patients receiving other drugs belonging to the same class as JEVTANA. JEVTANA should not be given to patients with hepatic impairment (total bilirubin 1 x ULN, or AST/SGOT and/or ALT/SGPT 1.5 ULN) (see CONTRAINDICATIONS). Patients with renal impairment: No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance (CL CR ): 50 to 80 ml/min). Data in patients with moderate (CL CR : 30 to 50 ml/min) and severe renal impairment (CL CR <30 ml/min) or end-stage renal failure is limited; therefore these patients should be treated with caution and monitored carefully during treatment (see also DOSAGE AND ADMINISTRATION, Special Populations; ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions sections). Monitoring and Laboratory Tests Monitoring of complete blood count is essential on a weekly basis during cycle 1 and before each treatment cycle and as required thereafter so that the dose can be adjusted, if needed (see WARNINGS AND PRECAUTIONS, Hematologic section). Page 8 of 43

9 Renal function should be monitored during JEVTANA therapy. Serum creatinine should be measured at baseline and with each blood count. JEVTANA treatment should be discontinued in case of renal failure grade 3 (see WARNINGS and PRECAUTIONS, Renal). ADVERSE REACTIONS Adverse Reaction Overview The Grade 3 adverse reactions reported in 5% of the patients in the phase III study including 371 patients in the JEVTANA group were neutropenia, leucopenia, anemia, febrile neutropenia, diarrhea, fatigue, and asthenia. The most common adverse reactions leading to treatment discontinuation were neutropenia and renal failure (see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, Clinical Trial Adverse Reactions sections). Clinical Trial Adverse Reactions Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates. The safety of JEVTANA in combination with prednisone or prednisolone was evaluated in 371 patients with castration resistant (hormone refractory) metastatic prostate cancer, in a randomized open label, controlled phase III study (TROPIC). Patients received a median duration of 6 cycles of JEVTANA or 4 of mitoxantrone. Very common ( 10%) grade 1-4 adverse reactions were anemia, leucopenia, neutropenia, thrombocytopenia, diarrhea, fatigue, nausea, vomiting, constipation, asthenia, abdominal pain, hematuria, back pain, anorexia, peripheral neuropathy (including peripheral sensory and motor neuropathy), pyrexia, dyspnea, dysgeusia, cough, arthralgia, and alopecia (see Table 1). The grade 3-4 adverse reactions reported in 5% of the patients who received JEVTANA were neutropenia, leucopenia, anemia, febrile neutropenia, diarrhea, fatigue and asthenia (see Table 1). Discontinuation of treatment due to adverse reactions occurred in 68 patients (18.3%) in the JEVTANA group and 31 patients (8.4%) in the mitoxantrone group. The most common adverse reactions leading to treatment discontinuation in the JEVTANA group were neutropenia and renal failure. Deaths due to causes other than disease progression within 30 days of last study drug dose were reported in 18 (4.9%) JEVTANA-treated patients and 3 (< 1%) mitoxantrone-treated patients. Page 9 of 43

10 The most common fatal adverse reactions in JEVTANA-treated patients were due to infections (n=5). The majority (4 of 5 patients) of fatal infection-related adverse reactions in the randomized clinical trial occurred after a single dose of JEVTANA. Table 1 provides the incidence of all adverse reactions and hematologic abnormalities occurring at higher rate (at least 2% higher) in patients receiving JEVTANA 25 mg/m 2 every 3 weeks with prednisone 10 mg daily (or prednisolone) compared to mitoxantrone 12 mg/m 2 every 3 weeks with prednisone 10 mg daily (or prednisolone) [TROPIC study]. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Page 10 of 43

11 Table 1. Incidence of reported adverse reactions and hematologic abnormalities in patients receiving JEVTANA in combination with prednisone (or prednisolone) and patients receiving mitoxantrone in combination with prednisone (or prednisolone) (at least 2% higher incidence rate in the JEVTANA group compared to mitoxantrone) [TROPIC study] Body System / Preferred term JEVTANA at 25 mg/m 2 every 3 weeks in combination with prednisone 10 mg daily (or prednisolone) All grades n (%) Blood and lymphatic system disorders n=371 grade 3/4 n (%) Mitoxantrone at 12 mg/m 2 every 3 weeks in combination with prednisone 10 mg daily (or prednisolone) All grades n (%) n=371 grade 3/4 n (%) Neutropenia a 347 (93.5%) 303 (81.7%) 325 (87.6%) 215 (58.0%) Anemia a 361 (97.3%) 39 (10.5%) 302 (81.4%) 18 (4.9%) Leucopenia a 355 (95.7%) 253 (68.2%) 343 (92.5%) 157 (42.3%) Thrombocytopenia a 176 (47.4%) 15 (4%) 160 (43.1%) 6 (1.6%) Febrile Neutropenia (7.5%) (1.3%) Gastrointestinal disorders Diarrhea 173 (46.6%) 23 (6.2%) 39 (10.5%) 1 (0.3%) Nausea 127 (34.2%) 7 (1.9%) 85 (22.9%) 1 (0.3%) Vomiting 84 (22.6%) 7 (1.9%) 38 (10.2%) 0 Constipation 76 (20.5%) 4 (1.1%) 57 (15.4%) 2 (0.5%) Abdominal Pain 43 (11.6%) 7 (1.9%) 13 (3.5%) 0 Dyspepsia 25 (6.7%) 0 6 (1.6%) 0 Abdominal Pain Upper 20 (5.4%) 0 5 (1.3%) 0 Hemorrhoids 14 (3.8%) 0 3 (0.8%) 0 Gastrooesophageal Reflux Disease 12 (3.2%) 0 3 (0.8%) 0 General disorders and administration site conditions Fatigue 136 (36.7%) 18 (4.9%) 102 (27.5%) 11 (3.0%) Asthenia 76 (20.5%) 17 (4.6%) 46 (12.4%) 9 (2.4%) Pyrexia 45 (12.1%) 4 (1.1%) 23 (6.2%) 1 (0.3%) Mucosal Inflammation 22 (5.9%) 1 (0.3%) 10 (2.7%) 1 (0.3%) Infections And Infestations Urinary Tract Infection 27 (7.3%) 4 (1.1%) 11 (3.0%) 3 (0.8%) Metabolism and nutrition disorders Anorexia 59 (15.9%) 3 (0.8%) 39 (10.5%) 3 (0.8%) Dehydration 18 (4.9%) 8 (2.2%) 10 (2.7%) 3 (0.8%) Page 11 of 43

12 Body System / Preferred term JEVTANA at 25 mg/m 2 every 3 weeks in combination with prednisone 10 mg daily (or prednisolone) All grades n (%) n=371 Musculoskeletal and connective tissue disorders grade 3/4 n (%) Mitoxantrone at 12 mg/m 2 every 3 weeks in combination with prednisone 10 mg daily (or prednisolone) All grades n (%) n=371 grade 3/4 n (%) Back Pain 60 (16.2%) 14 (3.8%) 45 (12.1%) 11 (3.0%) Arthralgia 39 (10.5%) 4 (1.1%) 31 (8.4%) 4 (1.1%) Muscle Spasms 27 (7.3%) 0 10 (2.7%) 0 Nervous System Disorders Dysgeusia 41 (11.1%) 0 15 (4.0%) 0 Neuropathy Peripheral 30 (8.1%) 2 (0.5%) 4 (1.1%) 1 (0.3%) Dizziness 30 (8.1%) 0 21 (5.7%) 2 (0.5%) Headache 28 (7.5%) 0 19 (5.1%) 0 Peripheral Sensory Neuropathy 20 (5.4%) 1 (0.3%) 5 (1.3%) 0 Renal and urinary tract disorder Hematuria 62 (16.7%) 7 (1.9%) 14 (3.8%) 2 (0.5%) Dysuria 25 (6.7%) 0 5 (1.3%) 0 Urinary Incontinence 9 (2.4%) 0 1 (0.3%) 0 Renal Failure Acute 8 (2.2%) 6 (1.6%) 0 0 Respiratory, Thoracic And Mediastinal Disorders Dyspnea 44 (11.9%) 5 (1.3%) 17 (4.6%) 3 (0.8%) Cough 40 (10.8%) 0 22 (5.9%) 0 Skin And Subcutaneous Tissue Disorders Alopecia 37 (10.0%) 0 18 (4.9%) 0 Vascular Disorders Hypotension 20 (5.4%) 2 (0.5%) 9 (2.4%) 1 (0.3%) a based on laboratory values Cardiac disorders and arrhythmias All grade events among cardiac disorders were more common on JEVTANA of which 6 patients (1.6%) had grade 3 cardiac arrhythmias. The incidence of tachycardia on JEVTANA was 1.6%, none of which were grade 3. The incidence of atrial fibrillation was 1.1% in the JEVTANA group. Cardiac failure events were more common on JEVTANA, the event term being reported for 2 patients (0.5%). One patient in the JEVTANA group died from cardiac failure. Fatal Page 12 of 43

13 ventricular fibrillation was reported in one patient (0.3%), and cardiac arrest in 2 patients (0.5%). None were considered related by the investigator. Gastrointestinal disorders Incidence of grade 3 diarrhea was 6.2%. No grade 4 diarrhea was reported and no fatal cases were reported. One case of grade 2 diarrhea was associated with a fatal electrolyte imbalance. General disorders and administration site conditions Peripheral oedema was observed at 9.2% incidence (all grades) in both groups, the incidence of grade 3 was 0.5% in JEVTANA arm and 0.3% in mitoxantrone arm. Pain was observed at an incidence of 5.4% and 4.9% in all grades and 1.1% and 1.9% in grades 3 in the JEVTANA arm and mitoxantrone arm, respectively. Investigations Decreased weight was observed at 8.6% and 7.5% in all grades and 0% and 0.3% in grades 3 in the JEVTANA and mitoxantrone arms, respectively. Nervous system disorders Grade 3-4 peripheral neuropathy was reported in 0.5% of patients. Renal and urinary tract disorders Renal failure was observed at 2.2% in all grades and 1.6% in grades 3 in the JEVTANA arm. Four cases with fatal outcome were reported in the randomized clinical trial. Hematuria: incidence of grade 3 hematuria was 1.9%. No fatal cases were reported in the JEVTANA-treated patients. Abnormal Hematologic and Clinical Chemistry Findings Neutropenia and associated clinical events: The incidence of grade 3 neutropenia based on laboratory data was 81.7%. The incidence of grade 3 clinical neutropenia and febrile neutropenia adverse reactions were respectively 21.3% and 7.5%. Neutropenia was the most common adverse reaction leading to drug discontinuation (2.4%). Neutropenic complications included neutropenic infections (0.5%), neutropenic sepsis (0.8%), and septic shock (1.1%), which in some cases resulted in a fatal outcome (one case of fatal neutropenia, one case of fatal febrile neutropenia, 2 cases of fatal neutropenic infection). The time to first occurrence of grade 3 neutropenia based on laboratory data showed that in most patients this event first occurred within the first 2 cycles of treatment. Page 13 of 43

14 The use of G-CSF has been shown to limit the incidence and severity of neutropenia (see DOSAGE AND ADMINISTRATION section). Anemia The incidence of grade 3 anemia based on laboratory abnormalities was 10.6% (54.2% of patients had any grade anemia at baseline). One fatal case was reported in the context of association with neutropenia and thrombocytopenia. Liver function abnormalities In the clinical study, the incidence of grade 3 increased AST, ALT, and bilirubin based on laboratory abnormalities were 0.7%, 0.9%, and 0.6%, respectively. Grade 4 increase in laboratory values of AST and ALT were reported in one patient each. Special Populations Geriatrics ( 65 years of age) Of the 371 patients treated with JEVTANA in the prostate cancer study, 240 patients were 65 years or over including 70 patients older than 75 years. The following adverse reactions reported at rates 5% higher in patients 65 years of age or greater compared to younger patients: fatigue (40.4% vs. 29.8%), neutropenia (24.2% vs. 17.6%), asthenia (23.8% vs. 14.5%), pyrexia (14.6% vs. 7.6%), dizziness (10.0% vs. 4.6%), urinary tract infection (9.6% vs. 3.1%) and dehydration (6.7% vs. 1.5%), respectively. The incidence of the following grade 3 adverse reactions were higher in patients 65 years of age compared to younger patients: neutropenia based on laboratory abnormalities (86.3% vs. 73.3%), clinical neutropenia (23.8% vs. 16.8%), febrile neutropenia (8.3% vs. 6.1%), cardiac disorders (2.9% vs 0%), infections and infestations (13.3% vs 4.6%) (see WARNINGS AND PRECAUTIONS, Special Populations and DOSAGE AND ADMINISTRATION, Special Populations sections). In the randomized clinical trial, 3 of 131 (2%) patients < 65 years of age and 15 of 240 (6%) patients 65 years of age died of causes other than disease progression within 30 days of the last JEVTANA dose. Post-Market Adverse Drug Reactions Gastrointestinal Disorders: Colitis, enterocolitis, gastritis, neutropenic enterocolitis have been observed. Gastrointestinal hemorrhage and perforation, ileus and intestinal obstruction have also been reported. Page 14 of 43

15 DRUG INTERACTIONS JEVTANA is extensively metabolized in the liver ( 95%), mainly by the CYP3A isoenzyme (80 to 90%). Therefore, concomitant drugs that are strong CYP3A inducers or inhibitors should be avoided and caution should be exercised in patients concurrently taking drugs known to be primarily metabolized through CYP3A (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics section). Overview In vitro studies have shown that JEVTANA is mainly metabolized through CYP3A. The metabolism of JEVTANA is modified by the concomitant administration of compounds which are known to be strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nelfinavir, ritonavir, saquinavir, voriconazole) or strong CYP3A inducers (e.g., rifampicin, carbamazepine, phenobarbital or phenytoin). Co-administration with strong CYP3A inhibitors should be avoided as they may increase cabazitaxel exposure (see Drug-Drug Interactions section below). Co-administration with strong CYP3A inducers should be avoided as they may decrease cabazitaxel exposure. A clinical drug-interaction study demonstrated that cabazitaxel (25 mg/m 2 administered as a single 1-hour infusion) did not modify the plasma levels of midazolam, a probe substrate of CYP3A. Therefore, JEVTANA at therapeutic doses when co-administered with CYP3A substrates in patients is not expected to have any clinical impact. However, there is no potential risk of inhibition of drugs that are substrates of other CYP enzymes (1A2, 2B6, 2C9, 2C8, 2C19, 2E1, and 2D6) as well as no potential risk of induction by JEVTANA on drugs that are substrates of CYP1A, CYP2C9, and CYP3A. In vitro JEVTANA did not inhibit the multidrug resistance proteins 1 and 2 (MRP1 and MRP2) or the organic cation transporter (OCT1). JEVTANA inhibited the transport of P-glycoprotein (P-gp) (digoxin, vinblastine), the breast cancer resistance protein (BCRP) (methotrexate) and the organic anion transporting polypeptides (OATP1B3) (CCK8) at concentrations at least 15 fold what was observed in clinical settings while it inhibited the transport of OATP1B1 (estradiol- 17β-glucuronide) at concentrations only five fold what was observed in clinical settings. Therefore the risk of interaction with substrates of MRP, OCT1, P-gp, BCRP substrates and OATP1B3, is unlikely in vivo at the dose of 25 mg/m 2. The in vitro study has demonstrated that the risk of interaction with substrates of OATP1B1 (e.g. statins, valsartan, repaglinide) is possible in vivo at the dose of 25 mg/m 2. The risk of interaction with OATP1B1 transporter may be limited to the infusion duration (1 hour) and up to 20 minutes after the end of the infusion. However, this has not been confirmed by an in vivo drug-drug interaction study. Page 15 of 43

16 Drug-Drug Interactions Prednisone/prednisolone administered at 10 mg daily did not affect the pharmacokinetics of JEVTANA. Repeated administration of ketoconazole (400 mg once daily), a strong CYP3A inhibitor, resulted in a 20% decrease in cabazitaxel clearance corresponding to a 25% increase in AUC. Concomitant administration of aprepitant, a moderate CYP3A inhibitor, had no effect on cabazitaxel clearance or exposure. Repeated administration of rifampin (600 mg once daily), a strong CYP3A inducer, resulted in an increase in cabazitaxel clearance of 21% corresponding to a decrease in AUC of 17%. JEVTANA did not inhibit in vitro the major biotransformation pathway of warfarin into 7-hydroxywarfarin, which is mediated by CYP2C9. Therefore, no pharmacokinetic interaction of JEVTANA on warfarin is expected in vivo. Vaccinations Administration of live or live-attenuated vaccines in patients immunocompromised by chemotherapeutic agents may result in serious or fatal infections. Vaccination with a live attenuated vaccine should be avoided in patients receiving JEVTANA. Killed or inactivated vaccines may be administered; however, the response to such vaccines may be diminished. Drug-Food Interactions Interactions with food have not been established. Drug-Herb Interactions Interactions with herbal products have not been established. Drug-Laboratory Interactions Interactions with laboratory tests have not been established. Page 16 of 43

17 DOSAGE AND ADMINISTRATION Dosing Considerations The use of JEVTANA should be confined to units specialized in the administration of cytotoxics and it should only be administered by a qualified healthcare professional experienced in the use of antineoplastic therapy (see Administration section below and SPECIAL HANDLING INSTRUCTIONS section). Premedication is recommended prior to treatment. Premedicate prior to each administration of JEVTANA with the following intravenous medications to reduce the incidence and severity of a hypersensitivity reaction: antihistamine (diphenhydramine 25 mg or equivalent), corticosteroid (dexamethasone 8 mg or equivalent) and with H2 antagonist (ranitidine or equivalent) (see WARNINGS AND PRECAUTIONS section). Antiemetics prophylaxis is recommended and can be given orally or intravenously as needed. Dosage modifications may be required if patients experience neutropenia, febrile neutropenia, diarrhea or peripheral neuropathy (see WARNINGS AND PRECAUTIONS and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment sections). Patients treated with JEVTANA may receive prophylactic G-CSF as per American Society of Clinical Oncology (ASCO) and/or current institutional guidelines, to reduce the risk or manage neutropenia complications (febrile neutropenia, prolonged neutropenia or neutropenic infection). The patients may also receive antibiotics when appropriate. Recommended Dose and Dosage Adjustment Recommended Dose The recommended dose of JEVTANA is 25 mg/m 2 administered as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone (or prednisolone) 10 mg administered daily throughout JEVTANA treatment. Dosage Adjustments Dosage modifications should be made if patients experience the following adverse reactions: Page 17 of 43

18 Table 2 - Recommended Dosage Modifications for adverse reaction in patients treated with JEVTANA Adverse reactions Dosage Modification Prolonged grade 3 neutropenia (greater than 1 week) despite appropriate medication including G-CSF Delay treatment until neutrophil count is > 1500 cells/mm 3, then reduce dosage of JEVTANA from 25 mg/m 2 to 20 mg/m 2. Febrile neutropenia or neutropenic infection Delay treatment until improvement or resolution, and until neutrophil count is > 1500 cells/mm 3, then reduce dosage of JEVTANA from 25 mg/m 2 to 20 mg/m 2. Grade 3 diarrhea or persisting diarrhea despite appropriate medication, fluid and electrolytes replacement Grade > 2 peripheral neuropathy Delay treatment until improvement or resolution, then reduce dosage of JEVTANA from 25 mg/m 2 to 20 mg/m 2. Delay treatment until improvement, then consider a dose reduction. Discontinue JEVTANA treatment if a patient continues to experience any of these reactions at 20 mg/m 2. Special Populations Pediatrics (< 16 years of age): The safety and the efficacy of JEVTANA in children have not been established. Geriatrics ( 65 years of age): No specific dose adjustment for the use of JEVTANA in elderly patients is recommended (see WARNINGS AND PRECAUTIONS, Special Populations, ADVERSE REACTIONS, Clinical Trial Adverse Reactions, Special Populations, ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions sections). Patients with hepatic impairment JEVTANA is extensively metabolized by the liver. No formal studies were conducted in patients with hepatic impairment. As a precautionary measure, JEVTANA should not be given to patients with hepatic impairment [bilirubin 1 x ULN, or AST/SGOT and/or ALT/SGPT 1.5 x ULN] (see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, Special Populations, ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions sections). Page 18 of 43

19 Patients with renal impairment JEVTANA is minimally excreted through the kidney. No dose adjustment is necessary in patients with mild renal impairment (creatinine clearance (CL CR ): 50 to 80 ml/min). Data in patients with moderate (CL CR : 30 to 50 ml/min) and severe renal impairment (CL CR <30 ml/min) or end stage renal disease is limited; therefore these patients should be treated with caution and monitored carefully during treatment (see WARNINGS AND PRECAUTIONS, Special Populations, ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions sections). Concomitant drug use Concomitant drugs that are CYP3A inducers or potent CYP3A inhibitors should be avoided (see DRUG INTERACTIONS section) Administration The final JEVTANA infusion solution should be administered intravenously as a 1-hour infusion at room temperature (see the two steps dilution process described below). Use an in-line filter of 0.22 micrometer nominal pore size (also referred to as 0.2 micrometer) during administration. Do not use PVC infusion containers or polyurethane infusion sets for the preparation and administration of the infusion solution. The JEVTANA infusion solution should be used immediately. However, in-use storage time can be longer under specific conditions mentioned in section STORAGE AND STABILITY. Please also refer to the SPECIAL HANDLING INSTRUCTIONS section. Dilution (2 steps process) Read this ENTIRE section carefully before mixing and diluting. JEVTANA requires TWO dilutions prior to administration. Follow the preparation instructions provided below. Note: Both the JEVTANA 60 mg/1.5 ml concentrate vial (fill volume: 73.2 mg cabazitaxel/1.83 ml) and the diluent vial (fill volume: 5.67 ml) contain an overfill to compensate for liquid loss during preparation. This overfill ensures that after dilution with the ENTIRE content of the accompanying diluent, there is an initial diluted solution containing 10 mg/ml of JEVTANA (see DOSAGE FORM, COMPOSITION AND PACKAGING section). The following 2-step dilution process must be carried out in an aseptic manner for preparing the infusion solution. Page 19 of 43

20 Step 1: Initial dilution of JEVTANA 60 mg/1.5 ml concentrated solution with the supplied diluent. Step 1.1 Inspect the JEVTANA 60 mg/1.5 ml concentrate vial and the supplied diluent. The concentrated solution should be clear (see STORAGE AND STABILITY section). Concentrate vial Diluent vial Step 1.2 Using a syringe fitted with a needle, aseptically withdraw the ENTIRE content of supplied diluent by partially inverting the vial. Diluent vial Step 1.3 Inject the ENTIRE content into the corresponding vial of JEVTANA 60 mg/1.5 ml concentrate. To limit foaming as much as possible when injecting the diluent, direct the needle onto the inside wall of the concentrate vial and inject slowly. Once reconstituted, the resultant solution contains 10 mg/ml of JEVTANA Concentratediluent mixture Diluent vial Step 1.4 Remove the syringe and needle and mix manually and gently by repeated inversions for at least 45 seconds until obtaining clear and homogeneous solution. Do not shake. Page 20 of 43

21 Step 1.5 Let this solution stand for a few minutes (approximately 5 minutes) to allow any foam to dissipate and check that the solution is homogeneous and clear. It is normal for foam to persist after this time period. It is not required that all foam dissipates prior to continuing the preparation process. This resulting concentrate-diluent solution contains 10 mg/ml of JEVTANA (at least 6 ml deliverable volume). It should be immediately diluted (within 1 hour) as detailed in Step 2. The solution is stable for 1 hour if stored at room temperature (15 C to 30 C) (see STORAGE AND STABILITY section). More than 1 vial of the initial diluted solution may be necessary to administer the prescribed dose. Discard any unused portion. Step 2: Preparation of the dilution solution for infusion. Step 2.1 Aseptically withdraw the required amount of initial diluted JEVTANA solution (10 mg/ml of JEVTANA), with a graduated syringe fitted with a needle. Since foam may persist on the wall of the vial of this solution following its preparation described in Step 1, it is preferable to place the needle of the syringe in the middle when extracting the solution. As an example, a dose of 45 mg of JEVTANA would require 4.5 ml of the concentrate-diluent mixture prepared following Step 1. More than 1 vial of the initial diluted solution may be necessary to administer the prescribed dose. Step 2.2 Inject in a sterile PVC-free container of either 5% dextrose solution or 0.9% sodium chloride solution for infusion. The concentration of the infusion solution should be between 0.10 mg/ml and 0.26 mg/ml. Page 21 of 43

22 Step 2.3 Remove the syringe and needle and mix the content of the infusion by gently inverting the bag or bottle. Step 2.4 As with all parenteral products, the resulting infusion solution should be inspected visually for particulate matter and discoloration prior to administration. Solution containing a precipitate or that is not clear should be discarded. After final dilution in the infusion bag/bottle, the infusion solution may be stored up to 8 hours at room temperature (including the 1 hour infusion). Chemical and physical stability of the infusion solution has been demonstrated for 48 hours under refrigerated conditions (this includes the 1-hour infusion which should be administered at room temperature) (see STORAGE AND STABILITY section). Discard any unused portion. Page 22 of 43

23 Table 3 - Two Steps Dilution Process Step Vial Size Volume of Diluent to be Added to Vial Step 1 Initial dilution Step 2 Preparation of the infusion solution Concentrated solution JEVTANA 60 mg/1.5 ml Solution after initial dilution 10 mg/ml of cabazitaxel (at least 6 ml deliverable volume) ENTIRE content of the supplied diluent 5% dextrose solution or 0.9% sodium chloride solution for infusion Approximate Available Volume At least 6 ml deliverable volume Depends on the dosage Nominal Concentration per ml 10 mg/ml of cabazitaxel The concentration of the infusion solution should be between 0.10 mg/ml and 0.26 mg/ml Incompatibilities / Compatibilities Always dilute JEVTANA 60 mg/1.5 ml concentrated solution with the ENTIRE content of the supplied diluent before adding to infusion solutions. JEVTANA must not be mixed with other drugs. JEVTANA contains polysorbate 80 which is known to increase the rate of di-(2- ethylhexyl) phtalate extraction (DEHP) from polyvinyl chloride (PVC). PVC infusion containers or polyurethane infusion sets should not be used for the preparation and administration of the infusion solution. Page 23 of 43

24 OVERDOSAGE Signs and Symptoms The anticipated complications of overdose would be exacerbation of adverse reactions as bone marrow suppression and gastrointestinal disorders. Management There is no known antidote to JEVTANA. In case of overdose, the patient should be kept in a specialized unit and closely monitored. Patients should receive therapeutic G-CSF as soon as possible after discovery of overdose. Other appropriate symptomatic measures should be taken. For management of a suspected drug overdose, contact your regional Poison Control Centre. ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action JEVTANA belongs to the taxanes class. It is prepared by semi synthesis with a precursor extracted from yew needles. JEVTANA is an antineoplastic agent that acts by disrupting the microtubular network in cells. JEVTANA binds to tubulin and promotes the assembly of tubulin into microtubules while simultaneously inhibiting their disassembly. This leads to the stabilization of microtubules, which results in the inhibition of mitotic and interphase cellular functions. Pharmacodynamics JEVTANA demonstrated a broad spectrum of antitumour activity against advanced human tumors xenografted in mice, including intracranial human glioblastomas. JEVTANA is active in docetaxel-sensitive tumors. In addition JEVTANA demonstrated activity in tumor models resistant to chemotherapy, including docetaxel. Pharmacokinetics A population pharmacokinetic analysis was carried out in 170 patients including patients with advanced solid tumors (n=69), metastatic breast cancer (n=34) and metastatic prostate cancer (n=67). These patients received doses of JEVTANA ranging from 10 to 30 mg/m 2 weekly or every 3 weeks. Page 24 of 43

25 Table 4 Summary of JEVTANA s Pharmacokinetic Parameters in Patients with Metastatic Prostate Cancer Dosage C max t ½ (h) AUC Clearance Volume of distribution 1-hour IV administration dose of JEVTANA at 25 mg/m ng/ml (CV: 107%) 95 hours 991 ng.h/ml (CV: 34%) 48.5 L/h (26.4 L/h/m² for a patient with a median BSA of 1.84 m²) 4870 L (2640 L/m² for a patient with a median BSA of 1.84 m²) at steady state Absorption: After a 1-hour IV administration dose of JEVTANA at 25 mg/m 2 in patients with metastatic prostate cancer (n=67), the mean C max was 226 ng/ml (coefficient of variation, CV 107%) and was reached at the end of the 1-hour infusion (T max ). The mean AUC was 991 ng.h/ml (CV: 34%). No major deviation to the dose proportionality was observed from 10 to 30 mg/m² in patients with advanced solid tumors (n=126). Distribution: The volume of distribution (Vss) was 4870 L (2640 L/m² for a patient with a median BSA of 1.84 m²) at steady state. In vitro, the binding of JEVTANA to human serum proteins was 89 to 92% and was not saturable up to ng/ml, which covers the maximum concentration observed in clinical studies. JEVTANA is mainly bound to human serum albumin (82.1%) and lipoproteins (87.9% for HDL, 69.8% for LDL, and 55.8% for VLDL). The in vitro blood-to-plasma concentration ratios in human blood ranged from 0.90 to 0.99 indicating that JEVTANA was equally distributed between blood and plasma. Metabolism: JEVTANA is extensively metabolized in the liver ( 95%), mainly by the CYP3A isoenzyme (80 to 90%). JEVTANA is the main circulating compound in human plasma. Seven metabolites were detected in plasma (including 3 active metabolites issued from O-demethylation), with the main one accounting for 5% of parent exposure. Around 20 metabolites of JEVTANA are excreted into human urine and feces. Based on in vitro studies, the potential risk of inhibition by JEVTANA at clinically relevant concentrations is possible towards drugs that are mainly substrate of CYP3A. JEVTANA does not inhibit other CYP enzymes. In addition, JEVTANA did not induce CYP isozymes (CYP1A, CYP2C, and CYP3A) in vitro. Excretion: After a 1-hour IV infusion [ 14 C]-cabazitaxel at 25 mg/m 2 in patients, approximately 80% of the administered dose was eliminated within 2 weeks. JEVTANA is mainly excreted in the feces as Page 25 of 43

26 numerous metabolites (76% of the dose); while renal excretion of JEVTANA and metabolites account for less than 3.7% of the dose (2.3% as unchanged drug in urine). Following a one-hour intravenous infusion, plasma concentrations of JEVTANA can be described by a three-compartment pharmacokinetic model characterized by rapid initial and intermediate phases with half-lives of 4 minutes and 2 hours respectively and by a long terminal phase with a half-life of 95 hours. JEVTANA had a high plasma clearance of 48.5 L/h (26.4 L/h/m² for a patient with a median BSA of 1.84 m²). Special Populations and Conditions Pediatrics: Safety and effectiveness of JEVTANA have not been established in children. Geriatrics: In the population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of JEVTANA between patients 65 years (n=100) and older (n=70; 57 patients from 65 to 75 years and 13 patients above 75 years) (see WARNINGS AND PRECAUTIONS, Special Populations, ADVERSE REACTIONS, Clinical Trial Adverse Reactions, DOSAGE AND ADMINISTRATION, Special Populations). Hepatic Insufficiency: No formal studies in patients with hepatic impairment have been conducted (see CONTRAINDICATIONS section). However, as JEVTANA is eliminated primarily via hepatic metabolism, increased exposure may be expected. Renal Insufficiency: JEVTANA is minimally excreted via the kidney (2.3% of the dose). No formal pharmacokinetic studies were conducted with JEVTANA in patients with renal impairment. However, the population pharmacokinetic analysis carried out in 170 patients that included 14 patients with moderate renal impairment (creatinine clearance in the range of 30 to 50 ml/min) and 59 patients with mild renal impairment (creatinine clearance in the range of 50 to 80 ml/min) showed that mild to moderate renal impairment did not have meaningful effects on the pharmacokinetics of JEVTANA (see WARNINGS AND PRECAUTIONS, Special Populations, DOSAGE AND ADMINISTRATION, Special Populations sections). Page 26 of 43

27 STORAGE AND STABILITY Before dilution Store the unopened vials at room temperature (15 C to 30 C). Do not refrigerate. After dilutions: For storage conditions of the initial diluted solution (step 1) and the final infusion solution (step 2), see below. Step 1: Stability of the initial diluted solution in the vial: After initial dilution of JEVTANA 60 mg/1.5 ml concentrated solution with the diluent, the resulting concentrate-diluent solution (10 mg/ml) should be used immediately. The solution is stable for 1 hour if stored at room temperature (15 C to 30 C). Discard any unused portion. Step 2: Stability of the solution in the infusion bag/bottle: After final dilution in the infusion bag/bottle (in either 0.9% sodium chloride or 5% dextrose solution), the infusion solution may be stored up to 8 hours (including the 1 hour infusion) at room temperature (15 C to 30 C). Chemical and physical stability of the infusion solution has been demonstrated for 48 hours under refrigerated conditions (2 C to 8 C) (this includes the 1-hour infusion which should be administered at room temperature). Discard any unused portion. As the infusion solution is supersaturated, it may crystallize over time. In this case, the solution must not be used and should be discarded. Page 27 of 43

28 SPECIAL HANDLING INSTRUCTIONS As for any other antineoplastic agent, caution should be exercised when handling and preparing JEVTANA solutions. The use of gloves is recommended. If JEVTANA at any step of its handling should come into contact with the skin, wash immediately and thoroughly with soap and water. If it should come into contact with mucous membranes, wash immediately and thoroughly with water. JEVTANA should only be prepared and administered by personnel trained in handling cytotoxic agents. Pregnant staff should not handle it. Any unused product or waste material should be disposed of in accordance with local requirements. DOSAGE FORMS, COMPOSITION AND PACKAGING Dosage Forms Two-vial formulation: One single-use concentrate vial of JEVTANA 60 mg /1.5 ml (40 mg/ml). The concentrated solution is a clear yellow to brownish-yellow oily solution. One single-use diluent vial. The diluent is a clear and colorless solution. Composition JEVTANA 60 mg /1.5 ml Concentrated Solution JEVTANA 60 mg/1.5 ml concentrated solution contains 60 mg cabazitaxel (anhydrous and solvent free) and 1.56 mg polysorbate 80 (including citric acid for ph adjustment) in a total volume of 1.5 ml (nominal volume). Each ml of the concentrated solution contains 40 mg cabazitaxel (anhydrous) and 1.04 mg polysorbate 80. Diluent The diluent for JEVTANA contains 13% (w/w) ethanol in water for injection, 4.5 ml (nominal volume). Page 28 of 43

29 Note: The JEVTANA 60 mg/1.5 ml concentrate vials are filled with a 22% excess (corresponding to 73.2 mg cabazitaxel for a total fill volume of 1.83 ml) and the diluent vials with a 26% excess (total fill volume 5.67 ml). Table 5 Nominal and actual fill volumes for Jevtana diluent and concentrate vials Diluent vial Concentrate vial Nominal volume 4.5 ml 1.5 ml (60 mg cabazitaxel) Actual fill volume 5.67 ml 1.83 ml (73.2 mg cabazitaxel) This fill volume has been established during the development of JEVTANA to compensate for liquid loss during preparation of the initial diluted solution. This overfill ensures that after dilution with the ENTIRE content of the accompanying diluent for JEVTANA, there is a minimal extractable premix volume of 6 ml containing 10 mg/ml which corresponds to the labeled amount of 60 mg per vial. Packaging One pack contains (2 vials): One concentrate vial: 1.5 ml (nominal volume) of JEVTANA 60 mg concentrated solution in 15 ml clear glass vial (type I) closed with a grey chlorobutyl rubber closure sealed by an aluminium cap covered with a light green plastic flip-off cap. One diluent vial: 4.5 ml (nominal volume) of diluent in 15 ml clear glass vial (type I) closed with a grey chlorobutyl rubber closer sealed by a gold color aluminium cap covered with a colourless plastic flip-off cap. Page 29 of 43

30 PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance Common name: Cabazitaxel Chemical name: (2α,5β,7β,10β,13α)-4-acetoxy-13-({(2R,3S)-3-[(tertbutoxycarbonyl) amino]-2-hydroxy-3-phenylpropanoyl}oxy)-1-hydroxy-7,10-dimethoxy- 9-oxo-5,20-epoxytax-11-en-2-yl benzoate - propan-2-one (1:1) Molecular formula: C 45 H 57 NO 14,C 3 H 6 O Molecular mass: (acetone solvate), (solvate free) Structural formula: O O NH O O O O OH O HO O H O O O O, O Physicochemical properties: White to almost white powder Practically insoluble in water and soluble in alcohol Lipophilic Page 30 of 43